Bioerodible contraceptive suppository

ABSTRACT

The invention relates to an intravaginally-dissolvable contraceptive suppository, a method of using said suppository, and an improved method of manufacturing said birth control device. The suppositories of the invention, which comprise a lyophilized foam and a contraceptive, have a dissolution time of at least about 2 hours, and up to about 24 hours, and provide superior protection against pregnancy.

BACKGROUND OF THE INVENTION

The invention relates to a bioerodible contraceptive device, and, moreparticularly, to an intravaginally-dissolvable contraceptive suppositorycomprising a lyophilized foam and a contraceptive, a method of usingsuch suppositories and a method for manufacturing them.

Vaginal contraceptives are well-known in the art, including, forexample, spermicidal creams and gels. These products can be used aloneor in conjunction with removable contraceptive devices, such asintrauterine devices. Although many of these products are readilyavailable without a prescription, there are several disadvantagesassociated with their use. The effectiveness of these products isgenerally limited to one or two hours. In addition, these creams or gelstend to melt very readily and, thus, are easily discharged from thevagina, thereby further limiting their effectiveness. Furthermore, thetendency to rapidly melt makes such products inconvenient and messy touse.

In the area of foams, although the use of foams and freeze-dried foamsto deliver various active ingredients is well-known, such foamsgenerally do not possess the requisite characteristics that would renderthem suitable for use as a contraceptive suppository. For example, inU.S. Pat. No. 4,642,903, Davies discloses the use of freeze-dried foamsfor dispensing a variety of active ingredients. However, Davis' foamsare designed to have very rapid dissolution rates (virtuallyinstantaneous) which would render his foam highly ineffective for use asa contraceptive. Moreover, it is not possible to control the degree ofaeration in Davis' foaming process; accordingly, using Davis' method itis not possible to control densities, dosage delivery rates anddissolution times of the foams which is critical to the manufacture of acontraceptive suppository.

Similarly, in U.S. Pat. No. 4,292,972, Pawelchak et al. discloses alyophilized foam sponge product containing sodiumcarboxymethylcellulose, pectin, gelatin and a pharmaceutical, that isintended primarily for use as a hemostatic agent. Unfortunately,Pawelchak's dispersions do not aerate readily; therefore, Pawelchak'sfreeze-dried foams possess poor structural integrity and dissolve tooquickly.

Accordingly, a need exists for a bioerodible vaginal contraceptivesuppository that, provides for the sustained and/or controlled releaseof a contraceptive, gives effective protection against pregnancy for atleast several hours, and which is not readily expelled. In addition,there is a need for a method of manufacturing such suppositories wherebythe dissolution time and the drug delivery rate of the suppository canbe substantially controlled and readily reproduced.

SUMMARY OF THE INVENTION

It has been found that an intravaginally dissolvable contraceptivesuppository comprising, a water-soluble lyophilized foam and acontraceptive. The suppository, having a density of about 0.001 to about0.1 gm/cc and a dissolution time of at least about 2 hours, can providefor the sustained and controlled release of a contraceptive for at least2 hours. The suppositories have dissolution times of at least about 2hours to about 24 hours, and therefore, are very slow to dissolve. Inaddition, upon dissolution, the suppositories form viscous gels whichmaintain good structural integrity intravaginally. Therefore, the userdoes not experience messy discharge and premature explusion of thedevice. To further facilitate retention and promote effectiveness, thesuppositories incorporate foams that render them muco-adherent.

Accordingly, the suppositories of the invention are comprised of foamsthat possess characteristics that render them ideal for incorporationinto a contraceptive suppository. Unlike the suppository devices of theprior art which are ineffectual after a couple of hours, the devices ofthe invention provide effective intravaginal contraception to the userfor a prolonged period following intercourse.

In addition, the disadvantages associated with prior methods ofmanufacture for active-ingredient-dispensing foams are overcome in thepresent invention. It has been determined that by using a continuous,enclosed mixer that is capable of operating under pressure to foam aliquid dispersion, it is possible to regulate certain foaming parametersand thereby control the liquid density of the foamed dispersions priorto lyophilization. The inventors have found that by controlling theliquid density of the foamed dispersion, it is possible to achieveexcellent control of the dissolution time, the dosage of activeingredient, as well as other properties of the suppositories.

Accordingly, it is an object of this invention to provide anintravaginal contraceptive device in the form of a suppository which iseffective for at least about 2 hours, and which has a dissolution timeof at least about 2 hours.

It is a further object of this invention to provide a contraceptivedevice in the form of a suppository which can be inserted intravaginallyby the user, which maintains its position in the vagina for a prolongedperiod, including during intercourse, and which is completely andnaturally soluble therein, thereby obviating the need for removal.

It is a further object of this invention to provide a method formanufacturing the intravaginal contraceptive device described herein,whereby the method provides for the production of suppositories havingsubstantially equivalent densities, dissolution times, dosages, andsoftness and flexibility properties.

Further objects and advantages of the present invention will be madeknown in the following description of the preferred embodiments andclaims.

DETAILED DESCRIPTION OF THE INVENTION

The contraceptive device of this invention comprises anintravaginally-dissolvable suppository comprising a water-solublelyophilized foam and a contraceptive, wherein the suppository has adensity of about 0.001 to about 0.1 gm/cc and a dissolution time of atleast about 2 hours. The suppositories of the invention provide for thesustained and/or controlled release of a contraceptive wherein thecontraceptive is effective for at least about 2 hours, and preferablyfor at least about 4 hours, after insertion into the vagina. The term"sustained release" means that the concentration of the contraceptive ismaintained at a relatively constant level in the vagina. The term"controlled release" means that the contraceptive is administered over aperiod of time.

The term suppository, as referred to herein, means any solid substance,of any shape, which is intended to be inserted into the vagina. Thesuppository of the invention is intended to be inserted by the user anddoes not require fitting by a physician as, for example, in the case ofan intrauterine device. It can be easily inserted digitally or with anapplicator. Furthermore, it is completely and naturally soluble in thevagina.

The suppository is designed to be inserted into the vagina, preferablyproximate to the cervix, prior to intercourse and maintainedintravaginally for at least about 2 hours following intercourse. Uponinsertion and contact with the moist mucous membrane (i.e., the lining)of the vagina, the suppository naturally and slowly begins to dissolveby fluid absorption. As the suppository dissolves, it continuallyreleases an effective amount of contraceptive (typically a spermicide)into the vaginal area, in a dosage sufficient to substantially reducethe likelihood of pregnancy resulting from intercourse.

In one preferred embodiment of the invention which particularlyfacilitates intravaginal retention, the suppository is designed toadhere to the mucous membrane of the vaginal cavity. Upon contact withmucus which is excreted by the mucous membrane, the muco-adherentsuppository hydrates, thus adhering the suppository to the membrane.This permits the device to be worn comfortably and prevents it frombeing expelled prematurely. Accordingly, delivery of the contraceptiveis not interrupted.

Upon dissolution, the lyophilized foam first forms a gel (i.e., acolloidal solution having the consistency of jelly), and then furtherdissolves into a liquid. The gel so formed possesses good structuralintegrity for a prolonged period prior to further dissolution to aliquid. For example, upon inspection at least 2 hours after thesuppositories of the invention have been placed in aqueous solution at3° C., a substantial amount of gel (at least about 10% by volume) stillremains visible to the naked eye. This gelling feature preventsundesireable premature leakage; in addition, it promotes intravaginalretention and thus, greater effectiveness, of the contraceptive.

The time required for the suppositories of the invention to attainsubstantially complete in-vitro dissolution to a liquid, (i.e., no gelis evident), as measured by the method described below, is referred toas "dissolution time." By applying the teachings of this invention,dissolution times of at least about 2 hours can be obtained, preferablyat least about 3.5 hours, more preferably at least about 8 hours, evenmore preferably at least about 20 hours, and most preferably at leastabout 24 hours. Moreover, in-vivo dissolution times are likely be evengreater.

The procedure described in USP XXII, 711 DISSOLUTION, Apparatus 1, fromU.S. Pharmacopeia was followed to determine the dissolution time. Thisprocedure uses an assembly consisting of a covered glass vessel (a Belljar), a motor, a drive shaft, a basket, and a constant temperature waterbath. The speed regulating device used allows the shaft rotation to beselected and maintained at a rate of 35 rpm. The basket is affixed tothe drive shaft. The vessel is filled with 200 ml of 1% (by weight)saline solution. The suppository is placed in a dry basket at thebeginning of each test, and the basket is immersed in the vesselcontaining the saline solution. The vessel is then immersed in aconstant temperature water bath set at 37° C. The sample is observed,and as dissolution takes place, the time for total gellation isrecorded. The test is allowed to continue and the time for totaldissolution of the gel is also recorded.

The dissolution time, density, and other physical characteristics of thesuppository like flexibility and softness are due, in part, to theidentity of the particular water-soluble polymer and contraceptiveselected, their respective amounts, and the novel manufacturing processdescribed herein.

The first step in producing the lyophilized foam suppository of theinvention comprises forming an aqueous dispersion comprising at leastone, and preferably several, water-soluble polymers, and acontraceptive. The term "aqueous dispersion" as used herein is meant toinclude dispersions (including solutions) in which the solvent is waterand optionally, water-miscible liquids.

Preferably, the polymer is initially added to the solvent and dispersed,followed by addition and dispersion of the contraceptive. If necessary,heat can be applied to the mixture to facilitate dispersion.

Cellulose, cellulose ethers, derivatives thereof, and polymers of thetype disclosed in U.S. Pat. No. 4,615,697, issued to Robinson, andcommercially available under the generic name "polycarbophil" aresuitable for use in the present invention. Other suitable polymersinclude polycarboxylated vinyl polymers, including polyacrylic acidpolymers, polyacrylic acid polymers that are lightly crosslinked with apolyalkenyl polyether, such as those commercially available from B.Goodrich, Cincinnati, Ohio, under the trademarks, Carbopol® 434, 934P,940 and 941, polysaccharide gums (such as natural plant exudatesincluding e.g., karaya gum, ghatti gum and the like), and seed gums(including e.g., guar gum, locust bean gum, psyllium seed gum and thelike). Cross-linked alginate gum gels of the type described in U.S. Pat.No. 3,640,741 to Etes are also suitable.

Preferably, the polymer is selected from the group consisting ofpolyurethanes, gelatins, celluloses and cellulose ethers, includinghydroxypropylmethylcellulose, sodium carboxymethylcellulose,methylcellulose, hydroxyethylcellulose , hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxyethylethylcellulose,hydroxypropylethylcellulose, carbopol, polyvinyl alcohol and derivativesthereof, dextran, chitosan and its derivatives, starch and itsderivatives, polyacrylamides, polyacrylates, agar, collagen,fibronectin, alginic acid, pectin, hyaluronic acid or mixtures thereof.

Foams comprised of cellulose ethers are especially preferred. Inparticular, it has been found that suppositories comprisinghydroxypropylmethylcellulose, a mixture of gelatin andhydroxy-propylmethylcellulose or a mixture ofhydroxypropylmethylcellulose and sodium carboxylmethylcellulose possessexcellent qualities, including good adherent properties.

Certain polymers, such as cellulose ethers generally andhydroxypropylmethylcellulose in particular, may be employed to provideliquid foams having good stability and structural integrity, and dryfoams with desirable softness. Other polymers, like gelatin, may beincorporated in the contraceptive devices of the invention to make themsufficiently rigid, so that the device can be inserted digitally or withan applicator without breaking or fracturing. One skilled in the art canreadily determine the polymeric ingredients and their amounts thatresult in a device having the preferred combination of suitableproperties.

Typically, polymer is added to the dispersion at a concentration ofabout 1% to 20% (by weight of the total dispersion includingcontraceptive), preferably about 2 to 16%, even more preferably about 2to 7%. At lower concentrations, there may be insufficient polymer toprepare a sturdy foam, whereas at higher concentrations, the dispersionmay be too viscous to foam under normal conditions.

The term contraceptive is meant to include any substance that tends orserves to prevent conception or impregnation in any animal, includingbut not limited to humans. Spermicides are preferred, especiallynonoxynol-9. Additional spermicides that may be incorporated into thesuppositories are described in U.S. Pat. No. 3,995,633 (Gougeon), whichis incorporated herein by reference.

The contraceptive may be provided in the dispersion at a concentrationof about 1% to about 25% (by weight of the total dispersion), with about5% to about 15% being preferred. The contraceptive may be present atfrom about 20% to about 95% by weight of the (dry) suppository, withabout 50% to about 80% by weight being preferred.

The amount of contraceptive incorporated into the suppository affectsthe in-vivo efficacy of the suppository, its tactile and structuralproperties, and the ease with which it may be manufactured. For example,suppositories containing relatively higher percentages of contraceptivemay be more efficacious and more flexible; however, such suppositoriesmay feel unpleasantly greasy to the user and have inadequate dissolutiontimes. Suppositories having lower percentages of contraceptive may betoo brittle; however, they may possess more desireable dissolutiontimes. Accordingly, it is necessary to empirically determine the amountof active ingredient that results in a device having the preferredcombination of suitable properties.

In practicing this invention, it has been determined that a suppositorycomprising a mixture of gelatin and hydroxypropylmethylcellulose in aninitial ratio of 12:1 (by weight in the aqueous dispersion), and about10-15% nonoxynol-9 (by weight in the aqueous dispersion) is preferred.Such a suppository is sufficiently soft, flexible, sturdy andmuco-adherent.

The suppositories of the invention may further contain additionalmaterials including, but not limited to, preservatives, fillers,excipients, binders, plasticizers, surfactants, wetting agents orpenetration agents. Methyl paraben is a preferred preservative.

All materials incorporated into the suppository should be blended into ahomogeneous mixture prior to foaming.

In order to ensure that the aqueous dispersion will subsequently foam,the viscosity of the dispersion should be maintained at about 4500 to7000 cps, preferably about 5000 to 6000 cps, most preferably about 5600cps, as measured on a Brookfield viscometer at 32° C. using a number 4spindle at 20 rpm. Accordingly, it may be necessary to cool thedispersion, preferably to about 32° to 35° C., with mixing in order tomaintain its viscosity.

After all materials to be incorporated into the suppository have beenblended into an aqueous dispersion having adequate viscosity forfoaming, the dispersion is then transferred to a continuous, enclosedmixer known as an "Oakes" foamer. An Oakes foamer is capable ofoperating under pressure to foam the dispersion and is typically used tomanufacture creamy, smooth food products like ice cream andmarshmallows. U.S. Pat. Nos. 2,572,049, 2,600,569, 2,679,866, and3,081,069 describe various Oakes foamers useful for practicing themethod of the invention, and the disclosures of these patents areincorporated herein by reference. The model referred to as the Oakes 2'Mixer, Model No. #2MT.5A is especially preferred for use in practicingthe invention.

An Oakes foamer is comprised of an electrical system, an air system anda product section. Generally it comprises a pump; a mixing chamber; ahead assembly having a rotor; a gas inlet; an outlet for the foameddispersion; means to measure pump speed, rotor speed, flow rate andpressure of an incoming gas; and means to measure the back pressure ofthe foamed dispersion.

The electrical system consists of a main power switch, and twoindependently variable speed controllers and motors with digitaltachometers to measure the rotor and pump speed.

The air system consists of a manual on/off toggle valve, pressureregulator and gauge, an adjustable flow valve and meter and a one way(check) valve.

The product section consists of a positive displacement pump; speedreducer; inlet piping; a back pressure gauge to monitor back pressure;and a mixing chamber. The gauge is isolated from the product bydiaphragm seal assembly.

A liquid dispersion is fed to the pump, transmitted through a line tothe mixing chamber wherein it is combined with air under pressure andmixed by the head assembly with rotor. In the mixing chamber, thedispersion is foamed, and the air and the dispersion are blended into asubstantially uniform, homogeneous mixture. From the mixing chamber, thefoamed dispersion is then sent to an outlet pipe.

It has been determined that the operating parameters of the mixer have asubstantial effect upon the density of the liquid foam, andconsequently, upon the properties of the suppositories produced. Forexample, increasing the pressure and/or flow rate of air into a fixedvolume of dispersion generally produces a more flexible, fasterdissolving suppository. Similarly, changing the pump speed or the rotorspeed also changes the liquid density of the foamed liquid dispersion.The use of an enclosed foamer (like an Oakes roamer) permits each ofthese process variables to be separately monitored and independentlyaltered in a controlled manner. Thus, it is possible to empiricallydetermine the settings of the foamer which will produce a foameddispersion having a desirable liquid density and, upon subsequentlyophilization, a suppository having suitable qualities. Moreover, theuse of such a foamer makes it possible to accurately reproduce thesettings so that a batch of suppositories having substantially identicalproperties, including dosages and dissolution times, is manufactured ineach manufacturing sequence.

It has been found that the suppositories of the invention should have a(dry) density of about 0.001 to about 0.1 gm/cc, preferably about 0.001to about 0.06 gm/cc, as determined using techniques which are well-knownto those of ordinary skill in the art. A suppository with a densitywithin these ranges possesses a good dissolution time. In addition, suchsuppositories are sufficiently sturdy, yet soft and flexible, so thatthe devices are comfortable to the user and yet do not readily break orfracture upon insertion.

Typically, in order to achieve suppositories with good physicalcharacteristics, good dissolution times, and which are sufficientlyefficacious at prolonged periods, foamer conditions are set as follows;pump speed about 25-30 rpm, air flow rate about 100-220 cc/min (at 100psig input pressure), and rotor speed about 1000-2000 rpm. The foam thatresults generates a back pressure of about 10-40 psig during extrusion.Of course, the conditions are approximate since operational variabilityoccurs in the meters during operation of the foamer. In addition, thedispersion probably has some air in it due to the dispersion formulationstep. Prior degassing will likely alter the density of the solution andrequire a change in the liquid/air ratio in the foamer.

Any of these process variables can be changed, thereby changing theliquid density of the foam. In order to determine how the liquid densityof the foam as well as the suppository produced from that foam areaffected, foams can be manufactured using the Oakes foamer wherein onlyone process variable is varied and all other parameters remain constant.

For example, a series of foams of varying liquid density can be producedby varying the flow rate of the incoming gas. The liquid density of theresulting foam is determined using techniques that are well-known tothose skilled in the art. A curve can be subsequently generated byplotting the density of the foamed liquid dispersion versus the flowrate.

The foamed dispersion produced from each run is then lyophilized (thatis, freeze-dried under vacuum). Upon lyophilization, the suppository(whose foamed liquid density is known) is evaluated to determine whetherit has certain desirable characteristics, including an adequatedissolution time. In this manner it is possible to empirically determinethe liquid density of the foam which, upon lyophilization, results in asuppository having suitable properties. Accordingly, the settingnecessary to foam the dispersion to the desired liquid density can bereadily determined empirically or from the graph, and more importantly,controlled by the operator of the foamer who can easily reset the gasflow rate (or any other process variable) to the appropriate setting.

Therefore, by using the method of the invention one can substantiallycontrol the liquid density of the foamed dispersions, and ultimately,the physical properties including dosages, contraceptive delivery ratesand dissolution times of the suppositories so produced.

Foaming can be continued until the back pressure gauge reaches anequilibrium value. Alternatively, one skilled in the art can readilydetermine when sufficient foaming has occurred by inspecting theviscosity of the foamed dispersion as it is extruded. Preferably, thedensity of the liquid foamed dispersion should range from about 0.1 toabout 1.0 gm/cc. Liquid foam densities of about 0.4-0.6 gm/cc are evenmore preferred.

In the next step, the foamed liquid dispersion is placed into areceptacle having a known volume ("unit dosage"). Since the liquiddensity of the foam and the volume of the receptacle are known, it is asimple calculation to determine the foam weight and the amount ofcontraceptive incorporated into each unit dosage.

Accordingly, one skilled in the art can readily manufacture batches ofdevices containing known and substantially equivalent dosages of activeingredient.

Although the liquid can be cast into sheet form, it is preferablyextruded through tygon tubing into a pre-formed mold. Various aluminum,plastic and release liner covered molds can be employed. Polyethylenemolds are preferred, since the suppositories easily release from thesemolds without cohesive failure.

It is also preferred to extrude the foam into compartmentalized trayswhereby the volume of one compartmental unit equals the volume of theresulting suppository. This prevents cold flow of the foam and thus, themanufacture of suppositories having nonuniform dimensions and dosages.

In another embodiment which favors contraceptive efficacy and wearingcomfort, the mold may be constructed in the size and shape of a tampon.

The foamed dispersion is then lyophilized in a freeze drier in order togenerate an open cell foam suppository which contains the contraceptive.A Virtis 800L-Freezemobile 12 is preferred. The freeze-drier shelves arechilled to below about -40° C. The condenser is chilled to below about-50° C. The filled molds are placed on the shelves and frozen to shelftemperature. The frozen foam is then exposed to the full vacuum (10-90millitorrs) of the unit. Once this vacuum is achieved, the shelftemperature is gradually increased to about room temperature andsublimation continues for at least about 15 hours, or until the sampletemperature reaches about 20°-25° C.

Thermal gravimetric analysis may be used to determine the water contentof the foams. It may also be used to determine the thermal stability ofthe suppositories by determining degradative weight loss.

The contraceptive content of the suppositories may be determined byultraviolet analysis of a solution of the dissolved foam.

The invention is further illustrated by the following examples which arenot intended to be limiting.

EXAMPLES Example 1 Preparation Of A Suppository Containing 10%Nonoxynol-9 (by weight of the liquid formulation).

Step 1. Dispersion Preparation

Deionized water (833 g) was preheated to 200° F., and 2 g of methylparaben was added with stirring. The solution was clear after about 5minutes, and 5 g of hydroxypropylmethylcellulose (Methocel E4M) wasadded and dispersed. Then 60 g of 275 bloom gelatin was dissolved withstirring. The solution was then cooled. When the clear solution hadcooled to about 35°-37° C., 100 g of nonoxynol-9 was added withstirring. The addition of the nonoxynol-9 caused the solution to becomeslightly turbid.

Step 2. Foaming Procedure

The solution of step 1, at about 31° C., was added to the hopper of anOakes Foamer, (Model 2MT. 5A). The solution was pumped through thesystem at a speed of about 21 rpm. The initial 100-150 ml was purged anddiscarded. The remainder was recirculated. The mixer assembly wasstarted, and the rotor was operated at 1053 rpm, until the viscosity hadincreased to a level sufficient to be foamed. Then air was added to thedispersion at an input pressure of 100 psig and a flow rate of 120cc/min. The foam was generated at a back pressure of 38 psig, andextruded into nalgene tubes 1.25 cm in diameter and 6.0 cm in length.

Step 3. Lyophilization Procedure

The liquid foam samples were then placed on the shelves of a Virtisfreeze drier (Unitop 800L with Freezemobile 12). These shelves werepre-chilled to -45° C. The condenser temperature was -65° C., and thesample temperature was -58° C. The frozen foam was lyophilized at fullvacuum (90 millitorr) to a temperature of 15° C. The drying time wasabout 48 hours. The samples were then removed from the tubes manually.

Example 2 Preparation Of A Suppository Containing 5% Nonoxynol-9 (byweight of the liquid formulation).

Step 1. Dispersion Preparation

The solution was prepared as in Example 1 except that 50 g ofnonoxynol-9 and 883 g of deionized water were formed into a dispersion.

Step 2. Foaming Procedure

The process in Example 1 was repeated with the following settings; pumpspeed 20 rpm, rotor speed 1082 rpm, air flow rate 70 cc/min and airpressure 100 psig. A back pressure of 10-12 psig was observed. Thesolution temperature at the time of addition to the foamer was 34° C.

Step 3. Lyophilization Procedure

The lyophilization conditions set forth in Example 1 were repeated.

Example 3 Preparation Of A Lower Density Suppository Containing 10%Nonoxynol-9 (by weight of the liquid formulation).

Step 1. Dispersion Preparation

The solution was prepared as in Example 1.

Step 2. Foaming Procedure

The solution was foamed in the manner set forth in Example 1 at 32° C.The following settings were employed: pump speed 20 rpm, rotor speed1075 rpm, air pressure 100 psig, and air flow rate 170 cc/min. A backpressure of 20-25 psig was observed. The liquid foam had a measureddensity of 0.555 gm/cc.

Step 3. Lyophilization Procedure

The liquid foam was lyophilized under the conditions of example 1. Thefull vacuum was 15 millitorrs. Drying time was about 40 hours.

Example 4 Preparation Of A Higher Density Suppository Containing 5%Nonoxynol-9 (by weight of liquid formulation).

Step 1. Dispersion Preparation

The dispersion was prepared under the same conditions set forth inExample 1, using the following quantities of ingredients: 15 g ofgelatin, 1.25 g of Methocel E4M, 0.5 g of methyl paraben (0.2%), 12.5 gof nonoxynol-9, and 221 g of deionized water.

Step 2. Foaming Procedure

No foaming was employed.

Step 3. Lyophilization Procedure

Conditions were the same as shown in Example 1.

Example 5 - Preparation Of A Higher Density Suppository Containing 10%Nonoxynol9 (by weight of the liquid formulation).

Step 1. Dispersion Preparation

The dispersion was prepared as described in Example 4. The quantities ofingredients were also the same as set forth in Example 4, except that 25g of nonoxynol-9 was added to 208 g of deionized water.

Step 2. Foaming Procedure

No foaming was employed.

Step 3. Lyophilization Procedure

The lyophilization conditions set forth in Example 4 were repeated.

Example 6 Preparation Of A Higher Density Suppository Containing 15%Nonoxynol-9 (by weight of the liquid formulation).

Step 1. Dispersion Preparation

The dispersion was prepared as in Example 4. The quantities ofingredients were the same as Example 4 except that 37.5 g of nonoxynol-9was added to 196 g of deionized water.

Step 2. Foaming Procedure

No foaming was employed.

Step 3. Lyophilization Procedure

Conditions of lyophilization were the same as Example 4.

Contraceptive Device Assay

A suppository was dissolved in water and analyzed by UV/VISspectroscopy. A 147.2 ug/ml solution of the device exhibited UVabsorbances at 225 nm and 275 nm due to nonoxynol-9, and anotherabsorbance at 255 nm due to gelatin. The spectra of the placebo foam andnonoxynol-9 confirmed the wavelengths.

A curve-fitting program was used to determine the concentration of thecontraceptive in the suppository. Thus, in one suppository thecalculated dose of nonoxynol-9 was 69% by weight (of the drysuppository) while the experimentally-determined value was 65%.

Thermal Gravimetric Analysis

The suppositories were subjected to thermal gravimetric analysis (TGA)at a heating rate of 10° C./min to 400° C. The onset of weight loss dueto water loss occurred between 50°-100° C., and was about 3-5% of thesample weight. Weight loss due to thermal degradation of a placebosuppository occurred at 256° C., while the nonoxynol-9 containingsuppository did not exhibit weight loss until the temperature reached291° C. This was apparently due to the presence of the nonoxynol-9 sinceits weight loss onset temperature was 321° C.

Effect Of The Density And The Contraceptive Content Of The LyophilizedFoam On Dissolution Time

The dissolution time of the suppository may be changed by changingeither the density of the lyophilized foam or the contraceptive content.For example, the dissolution time can be decreased by decreasing thedensity of the foam (i.e. increasing the air content of the foam) orincreasing the content of contraceptive. This is depicted in Table Iwhere suppositories containing 43% or 60% nonoxynol-9 (by weight ofsolids in the dry suppository) were prepared using the method describedherein, except that some samples were made without air.

                  TABLE I                                                         ______________________________________                                                                      Dissolution                                     Sample              Weight, g*                                                                              Time                                            ______________________________________                                        1.   43% nonoxynol-9 foam/no air                                                                      0.515     >23 h                                       2.   43% nonoxynol-9 foam/no air                                                                      0.468     >23 h                                       3.   60% nonoxynol-9 foam/no air                                                                      0.685     <23 h                                       4.   60% nonoxynol-9 foam/no air                                                                      0.688     <23 h                                       5.   43% nonoxynol-9 foam/                                                                            0.368     <23 h                                            70 cc/min air                                                            6.   43% nonoxynol-9 foam/                                                                            0.399     <23 h                                            70 cc/min air                                                            ______________________________________                                         *Each sample had the same constant volume.                               

Each of the samples gelled rapidly when placed in solution. After about2 hours, about 35% of the gel of samples 1, 2, 3 and 4 remained, whileabout 25% of the gel of samples 5 and 6 was left. After about 3.5 hours,about 25% of the gel of samples 1, 2, 3 and 4 remained, while about 15%of the gel of samples 5 and 6 was left. After about 23 hours, samples 3,4, 5 and 6 were completely dissolved, while about 5% of the gel remainedfrom samples 1 and 2.

Accordingly, the suppositories of the invention possess excellentin-vitro dissolution times.

Effect Of Foam Density And Spermicide Content On The Flexibility Of TheSuppository

The flexibility of the suppository can be affected by the density and bythe contraceptive content of the lyophilized foams. For example,tampon-shaped suppositories were tested in the horizontal position usingan Instron machine. Procedure ASTM-D-780 was used except that thecross-head speed was 5 inches per minute, and the chart speed was 8inches per minute. The tester was provided with a recorder adopted toprovide a stress/strain curve. The force that was measured was the forcerequired to cause failure in bending the suppository in the horizontalposition using a 3-point load device. The two support prongs were spacedapproximately one inch apart. The specimens to be tested were notconditioned. The test specimens were 1/2 inch in diameter and 2.2 incheslong.

                  TABLE II                                                        ______________________________________                                        Sample                Force, lbs                                              ______________________________________                                        60% nonoxynol-9 foam, no air                                                                        4.90                                                    43% nonoxynol-9 foam, no air                                                                        >5.00                                                   60% nonoxynol-9 foam, 170 cc/min                                                                    1.00                                                    43% nonoxynol-9 foam, 70 cc/min                                                                     3.35                                                    ______________________________________                                    

As shown above, increasing the amount of contraceptive and/or decreasingthe density of the foam resulted in a more flexible suppository.

IN-VIVO EFFICACY STUDIES

Primate mating studies were performed to determine the in-vivo efficacyof the suppositories. Suppositories containing either about 60% or 69%nonoxynol-9 (by weight in the lyophilized suppository) were placed inthe vagina of a primate prior to mating. The results are set forth inTable III below.

The "% motility" refers to the percentage of sperm that survive, and"forward progression" refers to the percentage of surviving sperm thatmove forward. The percentages of nonoxynol-9 indicate the percentage ofspermicide (by weight) that was added to the aqueous dispersion prior tofoaming.

                  TABLE III                                                       ______________________________________                                        Primate Mating Studies                                                                                    Sperm Conc                                        % Mortility % Forward Progression                                                                         (× 10.sup.6 /ml)                            ______________________________________                                        Foam containing 10% Nonoxynol-9                                               Zero Hour Single Mating                                                       0           0                48                                               0           0               117                                               0           0                54                                               Six Hour Single Mating                                                        22          90               48                                               52          90              144                                               42          92              141                                               Foam containing 15% Nonoxynol-9                                               Zero Hour Mating                                                              0           0               109                                               0           0               118                                               0           0                88                                               Four Hour Mating                                                              0           0               127                                               0           0               212                                               0           0               376                                               Eight Hour Mating                                                             0           0                85                                               0           0               347                                               25          50              215                                               0           0                99                                               Foam containing 15% Nonoxynol-9                                               Zero Hour Single Mating                                                       0           0                96                                               0           0               112                                               0           0                67                                               Foam containing 15% Nonoxynol-9                                               Zero Hour Single Mating                                                       0           0                96                                               0           0               112                                               0           0                67                                               Foam containing 15% Nonoxynol-9                                               Zero Hour Single Mating                                                       0           0                45                                               0           0               123                                               0           0                83                                               ______________________________________                                    

Zero hour single mating means that, upon insertion of the suppository,the primates immediately were permitted to commingle and mate once.Mating times of 4 or 6 hours means that, upon insertion of thesuppository, the primates were not permitted to commingle until theindicated time period had passed.

As indicated above, all of the suppositories were extremely effective atzero hour single mating. In addition, suppositories containing 69%nonoxynol-9 remained effective even at prolonged mating times of 4 to 8hours, whereas the suppository containing 60% of the contraceptive lostsome of its effectiveness.

The efficacy tests described in Table III indicate that suppositoriesmade from a dispersion containing a liquid concentration of about 15%nonoxynol-9 were most efficacious. The resulting suppositories weresufficiently flexible, however, they also tended to be greasy to thetouch and dissolved too quickly. Suppositories made from a liquiddispersion containing about 10% nonoxynol-9 were sufficiently flexibleand effective at zero hour single mating; but they were less effectiveat longer times. Suppositories made from a liquid dispersion containingabout 5% nonoxynol-9 were not evaluated in-vivo, but were found to bebrittle and dissolved even more slowly than the other samples.

The invention having now been fully described, it should be understoodthat it may be embodied in other specific forms or variations withoutdeparting from its spirit or essential characteristics. Accordingly, theembodiments described above are to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. An improved method for manufacturing a birthcontrol device comprised of water-soluble, lyophilized foam and acontraceptive, said method comprising the steps of:(a) forming anaqueous dispersion comprising from about 1% to about 25% by weight ofsaid contraceptive and from about 1% to about 20% by weight of at leastone water-soluble polymer; (b) providing a continuous, enclosed mixercapable of operating under pressure to foam the dispersion, saidcontinuous mixer comprising a pump; a mixing chamber; a head assemblyhaving a rotor; a gas inlet; an outlet for the foamed dispersion; meansto measure pump speed, rotor speed, and flow rate and pressure of anincoming gas; and means to measure the back pressure of the foameddispersion; (c) selecting a target density for the foamed liquiddispersion and a target dosage of contraceptive for said device, saidtarget density ranging from about 0.1 gm/cc to about 1.0 gm/cc; (d)setting a pump speed; (e) setting a rotor speed; (f) setting a pressureand flow rate for an incoming gas; (g) transferring said dispersion, ata viscosity sufficient for the dispersion to be foamed, to said mixer,and then foaming said dispersion until the density of the dispersion issubstantially equal to the target density, and the back pressure rangesfrom about 10 to about 40 psig; (h) placing said foamed dispersion intoa receptacle of known volume; and (i) lyophilizing said dispersion toproduce a lyophilized foam;whereby the dosage of contraceptive in thelyophilized foam is substantially equal to the target dosage.
 2. Themethod of claim 1 wherein step (a) comprises providing polymer in thedispersion at about 1% to about 15% by weight.
 3. The method of claim 1wherein step (a) comprises providing polymer in the dispersion at about2% to about 10% by weight.
 4. The method of claim 1 wherein step (a)comprises providing contraceptive in the dispersion at about 5% to about15% by weight.
 5. The method of claim 1 wherein step (h) comprisesextruding said dispersion into a compartmentalized tray comprised ofidentical units of known volume, whereby the dosage of contraceptive ineach unit is substantially equal to the target dosage.
 6. The method ofclaim 1 wherein the dispersion is lyophilized in a freeze-drier at fullvacuum for at least about 15 hours.
 7. The product produced by themethod of claim 1.